The intestine performs many functions, including the processes of digestion, absorption, and secretion. Yet, in addition, the intestine also serves as a barrier which prevents bacteria and endotoxin contained within the gut from reaching systemic organs as well as the portal and systemic circulations. Based, on clinical studies, the mucosal barrier to endotoxin and bacteria appears to be lost under certain circumstances resulting in systemic sepsis. In fact, life-threatening infections with gut-associated bacteria, in which no infective focus can be found even at autopsy, is a major clinical problem in burn and trauma victims, ICU patients and patients developing multiple organ failure. We and others have previously established that bacteria can translocate across the mucosal barrier and spread systemically under a variety of experimental conditions. Thus, that bacterial (endotoxin) translocation occurs appears clear, however, much remains to be learned about the basic biology of this process as well as its ultimate clinical relevance. Consequently, the central goals of this proposal are to 1) mechanistically investigate the systemic consequences of bacterial and endotoxin translocation on other organ systems and 2) to continue our investigations into the mechanisms by which intestinal barrier function is lost after thermal injury, hemorrhagic shock and endotoxin challenge. Specifically, AIM 1 will test the hypothesis that, under certain circumstances, intestinal injury can result in the gut becoming a cytokine generating organ; while AIM 2 will test the hypothesis that loss of intestinal barrier function and its sequelae result in distant organ injury which is mediated, at least in part, by endothelial cell activation/injury. In AIM 3, we will utilize both in vivo and in vitro models to investigate the pathobiology associated with loss of intestinal barrier function with special emphasis on the biology of oxidant mediated tissue injury. The investigations outlined in this proposal will help both clarify the role of intestinal barrier failure in the pathogenesis of distant organ injury as well as provide basic information on the biology and pathophysiology of bacterial translocation. Thus, these studies by providing basic information on the biology of the translocation process as well as the role of gut barrier failure in the evolution of distant organ injury will help in developing physiologically-based therapeutic strategies.